Multiple myeloma (MM) affected 14,400 new patients in the United States in 2001, with 50,000 total patients, and remains incurable despite conventional and high dose therapies. In order to overcome resistance to current therapies and improve patient outcome, novel biologically-based treatment approaches are needed which target mechanisms whereby MM cells grow and survive in the bone marrow (BM). Our preliminary in vitro and animal studies suggest a role for MM-host interactions in regulating MM cell growth, drug resistance, and migration in the BM. Moreover, our studies demonstrate that thalidomide and its potent immunomodulatory derivatives (IMiDs), proteasome inhibitor PS341, and arsenic trioxide As203 all target the MM cell in its BM milieu to overcome classical drug resistance both in vitro and in early clinical trials. In this context, we propose to carry out in vitro studies to characterize the role of the host BM microenvironment in promoting growth, survival, drug resistance, and migration of MM cells (Specific Aim 1) and then validate the growth, survival, drug resistance, and migratory signaling cascades triggered by MM cells in the host BM microenvironment as therapeutic targets (Specific Aim 2). These studies will provide the framework for validation of novel therapeutics targeting the MM-host BM interaction in vivo in animal models and in derived clinical trials (Specific Aim 3). These translational studies are directed to derive novel therapies to overcome drug resistance and improve outcome for patients with MM.